Biochimica et Biophysica Acta. Molecular Cell Research vol:1833 issue:8 pages:1924-1935
Proprotein convertases (PCs) form a group of serine endoproteases that are essential for the activation of proproteins into their active form. Some PCs have been proposed to be potential therapeutic targets for cancer intervention because elevated PC activity has been observed in many different cancer types and because many of the PC substrates, such as pro-IGF-1R, pro-TGF-beta, pro-VEGF, are involved in signaling pathways related to tumor development. Curcumin, reported to possess anticancer activity, also affects many of these pathways. We therefore investigated the effect of curcumin on PC activity. Our results show that curcumin inhibits PC activity in a cell lysate-based assay but not in vitro. PC zymogen maturation in the endoplasmic reticulum also appears to be inhibited by curcumin. Treating cells with thapsigargin or cyclopiazonic acid, two structurally unrelated inhibitors of the sarco- and endoplasmic reticulum Ca(2+)ATPase (SERCA), also hampered both the PC zymogen maturation and the PC activity. Importantly, curcumin, like the SERCA inhibitors, impaired ATP-driven (45)Ca(2+) uptake in the endoplasmic reticulum. These results indicate that curcumin likely restrains PC activity by inhibiting SERCA-mediated Ca(2+)-uptake activity. Experiments in three colon cancer cell lines confirm that curcumin inhibits both the (45)Ca(2+) uptake and PC activity, notably the processing of pro-IGF-1R. Both curcumin and thapsigargin inhibit the anchorage-independent growth of these three colon carcinoma cell lines. In conclusion, our findings indicate that curcumin inhibits PC zymogen maturation and consequently PC activity and that its inhibitory effect on Ca(2+) uptake into the ER allows and is sufficient to explain this phenomenon.